Project Summary: Radiotracers containing [18F]-labeled electron-rich aromatic rings are among the most highly sought-after PET imaging agents. For example, the development of a clinical synthesis of 6-[18F]fluoro- L-DOPA has been a challenging and high-profile target in the PET community for more than 20 years. Despite the great importance of [18F]-labeled electron rich arenes, there are very few radiosynthesis methods for accessing these structures. The grant builds on an existing collaboration between the physical sciences (Chemistry, Sanford) and life sciences (Radiology/Medical Imaging, Scott) at the University of Michigan, bringing their collective expertise to bear on this problem. The overall objective of the proposed research is to address this critical need by developing nucleophilic radiofluorination methods that (a) enable radiochemists to 18F-label electron rich aromatic rings starting from readily available, stable precursor molecules and (b) can be automated, validated, and translated to radiochemistry manufacturing facilities for use by non-chemists to synthesize clinical radiotracer doses. The central hypothesis of this application is that copper mediated radiofluorination methods will uniquely enable this team to achieve these objectives. The proposed research will develop Cu-mediated methods for radiolabeling (mesityl)(aryl)iodonium salts (Aims 1 and 2) as well as aryl iodides, aryl boronic acids and aryl stannanes (Aim 3) with 18F?. The work is significant because it entails development of novel methods for the synthesis of previously inaccessible (or difficult to access) 18F-labeled PET radiotracers of clinical interest: 4-[18F]fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG; cardiac regional nerve density), 6-[18F]fluoro-L-DOPA ([18F]F-DOPA; dopaminergic pathway), [18F]2'-methoxyphenyl- (N-2'-pyridinyl)-p-fluoro-benzamidoethylpiperazine ([18F]MPPF; 5-HT1A receptor), (4- [18F]fluorophenyl)triphenylphosphonium chloride ([18F]BFPET; mitochondrial voltage sensor), [18F]octreotide ([18F]TOC; somatostatin 2 receptors in, for example, neuroendocrine tumors); pre-clinical interest: new radiotracers for the GAT-1 GABA transporter and dopamine D3 receptor, and targets of interest to the pharmaceutical industry (BACE, orexin receptors). These goals will be accomplished through a variety of innovations including: (a) the development of novel copper-mediated methods for the nucleophilic radiofluorination of electron rich arenes (including new methods for the generation and utilization of Ag18F), (b) the mechanistically-driven optimization of these new radiofluorination reactions and (c) translation of these methods to clinically validated radiosyntheses (automated synthesis of cGMP-compliant clinical doses). Overall, this project will deliver four novel Cu-mediated methods for synthesizing 18F-labeled radiotracers and validated clinical synthesis of numerous important radiotracers. Both of these deliverables will expand the utility of PET imaging for the detection, treatment, and prevention of disease.